Development and Mechanist Validation of Next Generation Allosteric PRC2 Inhibitors for Cancer Epigenetics

About This Grant

Despite advances in oncology, there remains an urgent need for innovative anticancer strategies that can overcome resistance and improve patient outcomes. Epigenetic dysregulation is a key driver of tumorigenesis, with aberrant gene silencing and altered chromatin architecture contributing to cancer progression. Among epigenetic marks, trimethylation of lysine 27 on histone 3 (H3K27me3), installed by the polycomb repressive complex 2 (PRC2), is strongly linked to poor prognosis in diverse malignancies. Hyperactivation of PRC2, particularly through EZH2 overexpression, leads to widespread repression of tumor suppressor genes, driving cancer cell proliferation and therapeutic resistance. Although current PRC2 inhibitors mostly target the EZH2 catalytic domain, prolonged use frequently induces resistant mutations that limit clinical efficacy.To address this challenge, our laboratory has identified DAB003-8C, a potent and cell-permeable stapled peptide designed to target the SANT1L domain of EZH2, offering a first-in-class allosteric mechanism of PRC2 inhibition. This proposal aims to systematically optimize DAB003-8C and its derivatives through structure-activity studies, strategic chemical modifications, and computational design—yielding analogs with enhanced potency, stability, and permeability. Mechanistic investigations will clarify their allosteric inhibition and selectivity, employing biochemical and biophysical assays, protein-binding studies, cellular imaging, and stability assessments. Complementary cellular assays will probe the impact of these compounds on H3K27me3 levels, EZH2- mediated pathways, and gene expression profiles in a range of cancer cell models, integrating functional readouts such as proliferation, survival, and migration. Ultimately, this research will generate mechanistic insight into allosteric control of PRC2 and advance the development of next-generation inhibitors with broad translational relevance. The project will deepen our understanding of epigenetic regulation in cancer and facilitate the future discovery of targeted chemotherapeutics for overcoming resistance and improving patient care.